Guanylate-binding protein 1 (Gbp1) contributes to cell-autonomous immunity against Toxoplasma gondii

PLoS Pathog. 2013;9(4):e1003320. doi: 10.1371/journal.ppat.1003320. Epub 2013 Apr 25.

Abstract

IFN-γ activates cells to restrict intracellular pathogens by upregulating cellular effectors including the p65 family of guanylate-binding proteins (GBPs). Here we test the role of Gbp1 in the IFN-γ-dependent control of T. gondii in the mouse model. Virulent strains of T. gondii avoided recruitment of Gbp1 to the parasitophorous vacuole in a strain-dependent manner that was mediated by the parasite virulence factors ROP18, an active serine/threonine kinase, and the pseudokinase ROP5. Increased recruitment of Gbp1 to Δrop18 or Δrop5 parasites was associated with clearance in IFN-γ-activated macrophages in vitro, a process dependent on the autophagy protein Atg5. The increased susceptibility of Δrop18 mutants in IFN-γ-activated macrophages was reverted in Gbp1(-/-) cells, and decreased virulence of this mutant was compensated in Gbp1(-/-) mice, which were also more susceptible to challenge with type II strain parasites of intermediate virulence. These findings demonstrate that Gbp1 plays an important role in the IFN-γ-dependent, cell-autonomous control of toxoplasmosis and predict a broader role for this protein in host defense.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy-Related Protein 5
  • Bone Marrow Cells / cytology
  • Cells, Cultured
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • Immunity, Cellular
  • Interferon-gamma / metabolism*
  • Macrophage Activation / immunology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Toxoplasma / immunology*
  • Toxoplasma / pathogenicity
  • Toxoplasmosis / immunology*
  • Toxoplasmosis / parasitology

Substances

  • ATG5 protein, human
  • Autophagy-Related Protein 5
  • Gbp2b protein, mouse
  • Microtubule-Associated Proteins
  • Interferon-gamma
  • Protein-Serine-Threonine Kinases
  • ROP18 protein, Toxoplasma gondii
  • GTP-Binding Proteins